Novel composition and method for stabilizing the same

ABSTRACT

Disclosed is a novel composition comprising a novel bi-cyclic compound, which is expected to be pharmaceutically active, and a glyceride. The stability of the bi-cyclic compound can be improved significantly by dissolving the same in a glyceride.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a continuation of U.S. Application No. 13/289,386 filed Nov. 4,2011, which is a continuation of U.S. application Ser. No. 12/144,000filed Jun. 23, 2008, which is a continuation of U.S. application Ser.No. 10/383,581 filed Mar. 10, 2003, now U.S. Pat. No. 7,417,067 issuedAug. 26, 2008, which is a divisional of U.S. application Ser. No.09/688,351 filed Oct. 16, 2000, now U.S. Pat. No. 6,583,174 issued Jun.24, 2003, which claims benefit of Provisional Application No. 60/159,549filed Oct. 15, 1999; the above noted prior applications are all herebyincorporated by reference.

FIELD OF THE INVENTION

The present invention relates to a novel composition comprising a novelbi-cyclic compound and a glyceride, and a method for stabilizing thebi-cyclic compound comprising the step admixing the same with aglyceride.

BACKGROUND ART

A glyceride has been applied widely in the medical field and is usefulas an immediate alimentation or an entero-protecting agent(JP-A-4-210631). In addition, it is also useful as a solvent for variouspharmaceutically active compounds such as active vitamin Ds, diazepam,thiazole derivatives, prostaglandins or flavonoids, as a diluent for acapsule preparation, as a vehicle of eye drop, and as a stabilizingagent (JP-A-5350141, JP-A-53-75320, U.S. Pat. No. 4,248,867, JPA-55-136219, U.S. Pat. No. 4,247,702, JP-A-59-137413, JP-A-02-204417,JP-A-04-46122, U.S. Pat. No. 5,411,952, U.S. Pat. No. 5,474,979 and U.S.Pat. No. 5,981,607).

However, the prior arts are silent on the effect of glycerides on thenovel pharmaceutically active bicyclic compounds.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a novel compositioncomprising a certain bi-cyclic compound having a pharmacologicalactivity and a glyceride, and a method for stabilizing the bi-cycliccompound by admixing the same with a glyceride.

Another object of the present invention is to provide a novel compoundhaving a pharmacological activity.

This inventor studied to improve the stability of a novel bi-cycliccompound and found that a composition comprising the bi-cyclic compoundand a glyceride can attain the above object.

Accordingly, the present invention provides a novel compositioncomprising a bi-cyclic compound represented by the formula (I):

wherein, A is —CH₂OH, —COCH₂OH, —COOH or a functional derivativethereof;

X₁ and X₂ are hydrogen atom, lower alkyl or halogen atom;

V₁ and V₂ are carbon or oxygen atoms;

W₁ and W₂ are

wherein R₄ and R₅ are hydrogen atom, hydroxy, halogen atom, lower alkyl,lower alkoxy or hydroxy (lower) alkyl with the proviso that R₄ and R₅are not hydroxy or lower alkoxy at the same time;

Z is a carbon, oxygen, sulfur or nitrogen atom;

R₁ is a saturated or unsaturated bivalent lower-medium aliphatichydrocarbon residue which is unsubstituted or substituted with halogen,an alkyl group, hydroxy, oxo, aryl or heterocyclic group;

R₂ is a saturated or unsaturated, lower or medium aliphatic hydrocarbonresidue which is unsubstituted or substituted with halogen atom, oxo,hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, lower cycloalkyl,lower cycloalkyloxy, aryl, aryloxy, heterocyclic group orheterocyclic-oxy group; lower cycloalkyl; lower cycloalkyloxy; aryl,aryloxy, heterocyclic group or heterocyclic-oxy group;

R₃ is a hydrogen atom, a lower alkyl, lower cycloalkyl, aryl orheterocyclic group;

and a glyceride, and a method for stabilizing the above-specifiedbi-cyclic compound by means of dissolving said compound in a glyceride.

The present invention also provides a novel bi-cyclic compoundrepresented by the above formula (I).

In the above formula (I), the term “unsaturated” in the definitions forR₁ and R₂ is intended to include at least one or more double bondsand/or triple bonds that are isolatedly, separately or serially presentbetween carbon atoms of the main and/or side chains. According to theusual nomenclature, an unsaturated bond between two serial positions isrepresented by denoting the lower number of the two positions, and anunsaturated bond between two distal positions is represented by denotingboth of the positions.

The term “lower or medium aliphatic hydrocarbon” refers to a straight orbranched chain hydrocarbon group having 1 to 14 carbon atoms (for a sidechain, 1 to 3 carbon atoms are preferable) and preferably 1 to 10,especially 2 to 8 carbon atoms for R₁ and 1 to 10, especially 1 to 8carbon atoms for R₂.

The term “halogen atom” covers fluorine, chlorine, bromine and iodine.Particularly preferable is a fluorine atom.

The term “lower” throughout the specification is intended to include agroup having 1 to 6 carbon atoms unless otherwise specified.

The term “lower alkyl” refers to a straight or branched chain saturatedhydrocarbon group containing 1 to 6 carbon atoms and includes, forexample, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,pentyl and hexyl.

The term “lower alkoxy” refers to a group of lower alkyl-O—, whereinlower alkyl is as defined above.

The term “hydroxy(lower)alkyl” refers to a lower alkyl as defined abovewhich is substituted with at least one hydroxy group such ashydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and1-methyl-1-hydroxyethyl.

The term “lower alkanoyloxy” refers to a group represented by theformula RCO—O—, wherein RCO— is an acyl group formed by oxidation of alower alkyl group as defined above, such as acetyl.

The term “lower cycloalkyl” refers to a cyclic group formed bycyclization of a lower alkyl group as defined above but contains threeor more carbon atoms, and includes, for example, cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl.

The term “lower cycloalkyloxy” refers to the group oflower-cycloalkyl-O—, wherein lower cycloalkyl is as defined above.

The term “aryl” may include unsubstituted or substituted aromatichydrocarbon rings (preferably monocyclic groups), for example, phenyl,naphthyl, tolyl, xylyl. Examples of the substituents are halogen atomand halo(lower)alkyl, wherein halogen atom and lower alkyl are asdefined above.

The term “aryloxy” refers to a group represented by the formula ArO—,wherein Ar is aryl as defined above.

The term “heterocyclic group” may include mono- to tri-cyclic,preferably monocyclic heterocyclic group which is 5 to 14, preferably 5to 10 membered ring having optionally substituted carbon atom and 1 to4, preferably 1 to 3 of 1 or 2 type of hetero atoms selected fromnitrogen atom, oxygen atom and suffer atom. Examples of the heterocyclicgroup include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, imidazolyl, pyrazolyl, furazanyl, pyranyl, pyridyl,pyridazinyl, pyrimidyl, pyrazinyl, 2-pyrrolinyl, pyrrolidinyl,2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl,piperidino, piperazinyl, morpholino, indolyl, benzothienyl, quinolyl,isoquinolyl, purinyl, quinazolinyl, carbazolyl, acridinyl,phenanthridinyl, benzimidazolyl, benzimidazolonyl, benzothiazolyl,phenothiazinyl. Examples of the substituent in this case includehalogen, and halogen substituted lower alkyl group, wherein halogen atomand lower alkyl group are as described above.

The term “heterocyclic-oxy group” means a group represented by theformula HcO—, wherein Hc is a heterocyclic group as described above.

The term “functional derivative” of A includes salts (preferablypharmaceutically acceptable salts), ethers, esters and amides.

Suitable “pharmaceutically acceptable salts” include conventionally usednon-toxic salts, for example a salt with an inorganic base such as analkali metal salt (such as sodium salt and potassium salt), an alkalineearth metal salt (such as calcium salt and magnesium salt), an ammoniumsalt; or a salt with an organic base, for example, an amine salt (suchas methylamine salt, dimethylamine salt, cyclohexylamine salt,benzylamine salt, piperidine salt, ethylenediamine salt, ethanolaminesalt, diethanolamine salt, triethanolamine salt,tris(hydroxymethylamino)ethane salt, monomethyl-monoethanolamine salt,procaine salt and caffeine salt), a basic amino acid salt (such asarginine salt and lysine salt), tetraalkyl ammonium salt and the like.These salts may be prepared by a conventional process, for example fromthe corresponding acid and base or by salt interchange.

Examples of the ethers include alkyl ethers, for example, lower alkylethers such as methyl ether, ethyl ether, propyl ether, isopropyl ether,butyl ether, isobutyl ether, t-butyl ether, pentyl ether and1-cyclopropyl ethyl ether; and medium or higher alkyl ethers such asoctyl ether, diethylhexyl ether, lauryl ether and cetyl ether;unsaturated ethers such as oleyl ether and linolenyl ether; loweralkenyl ethers such as vinyl ether, allyl ether; lower alkynyl etherssuch as ethynyl ether and propynyl ether; hydroxy(lower)alkyl etherssuch as hydroxyethyl ether and hydroxyisopropyl ether; lower alkoxy(lower)alkyl ethers such as methoxymethyl ether and 1-methoxyethylether; optionally substituted aryl ethers such as phenyl ether, tosylether, t-butylphenyl ether, salicyl ether, 3,4-di-methoxyphenyl etherand benzamidophenyl ether; and aryl(lower)alkyl ethers such as benzylether, trityl ether and benzhydryl ether.

Examples of the esters include aliphatic esters, for example, loweralkyl esters such as methyl ester, ethyl ester, propyl ester, isopropylester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester and1-cyclopropylethyl ester; lower alkenyl esters such as vinyl ester andallyl ester; lower alkynyl esters such as ethynyl ester and propynylester; hydroxy(lower)alkyl ester such as hydroxyethyl ester; loweralkoxy (lower) alkyl esters such as methoxymethyl ester and1-methoxyethyl ester; and optionally substituted aryl esters such as,for example, phenyl ester, tosyl ester, t-butylphenyl ester, salicylester, 3,4-di-methoxyphenyl ester and benzamidophenyl ester; andaryl(lower)alkyl ester such as benzyl ester, trityl ester and benzhydrylester. Examples of the amides are mono- or di-lower alkyl amides such asmethylamide, ethylamide and dimethylamide; arylamides such as anilideand toluidide; and alkyl- or aryl-sulfonylamides such asmethylsulfonylamide, ethylsulfonyl-amide and tolylsulfonylamide.

Preferred A is —COON, —CH₂OH, or its pharmaceutically acceptable salt,ester, ether or amide.

Preferred combination of X₂ and X₂ is that at least one of X₂ and X₂ ishalogen atom, and more preferably, both of them are halogen, especiallyfluorine atoms.

Preferred W₁ is ═O, or where one of R₄ and R₅ is hydrogen, another ishydroxy,

Preferred W₂ is where R₄ and R₅ are both hydrogen atoms,

Preferred Z is an oxygen atom.

Preferred R₁ is an unsubstituted saturated or unsaturated bivalentlower-medium aliphatic hydrocarbon residue. It may preferably have 1-10carbon atoms, more preferably, 2-8 carbon atoms.

Examples of R₁ include, for example, the following groups:

—CH₂—CH₂—,

—CH₂—CH₂—CH₂—CH₂—,

—CH₂—CH═CH—CH₂—,

—CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—,

—CH₂—CH═CH—CH₂—CH₂—CH₂—,

—CH₂—CH₂—CH₂—CH₂—CH═CH—,

—CH₂—C≡C—CH₂—CH₂—CH₂—,

—CH₂—CH₂—CH₂—CH₂—CH(CH₃)—CH₂—

—CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—,

—CH₂—CH═CH—CH₂—CH₂—CH₂—CH₂—CH₂—,

—CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—CH═CH—,

—CH₂—C≡C—CH₂—CH₂—CH₂—CH₂—CH₂—,

—CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—CH₂(CH₃)—CH₂—

Preferred R₂ is a saturated or unsaturated bivalent lower-mediumaliphatic hydrocarbon residue. It may preferably have 1-10 carbon atoms,more preferably, 1-8 carbon atoms.

Preferred R₃ is a hydrogen atom.

The bi-cyclic compounds according to the present invention encompass notonly the compounds represented by the above formula (I) but also opticisomers, steric isomers, and tautomeric isomers thereof.

It has been known that a bi-cyclic compound having the formula as shownbelow (Tautomer II) may be in equilibrium with its tautomeric isomer,13,14-dihydro-15-keto-prostaglandin compound(tautomer I) (U.S. Pat. No.5,166,174, U.S. Pat. No. 5,225,439, U.S. Pat. No. 5,284,858, U.S. Pat.No. 5,380,709, U.S. Pat. No. 5,428,062 and U.S. Pat. No. 5,886,034,these cited references are herein incorporated by reference.)

However, it has been discovered that in the absence of water, thetautomeric compounds as above exist predominantly in the form of thebi-cyclic compound. In aqueous media, it is believed that hydrogenbonding occurs between the water molecule and, for example, the ketogroup at the hydrocarbon chain, thereby hindering bi-cyclic ringformation. In addition, it is believed that the halogen atom(s) at X₁and/or X₂ promote bi-cyclic ring formation, such as the compound 1 or 2below. The bi-cyclic/mono-cyclic structures, for example, may be presentin a ratio of 6:1 in D₂O; 10:1 in CD₃OD-D₂O and 96:4 in CDCl₃.Accordingly, a preferable embodiment of the present invention is thecomposition in which the bi-cyclic form is present in ratio ofbi-cyclic/mono-cyclic of at least 50:50, preferably 90:10, or evengreater to substantially all bi-cyclic compound; 100% bi-cyclic compoundis within this invention.

Preferred embodiment of the compound of the present invention includethe Compounds 1 and 2 shown below:

Compound 1:

7-[(1R,3R,6R,7R)-3-(1,1-difluoropentyl)-3-hydroxy-2-oxabicyclo[4.3.03nonane-8-one-7-yl]heptanoic acid

Compound 2:

7-[(1R,6R,7R)-3-[(3S)-1,1-difluoro-3-methylpentyl]-3-hydroxy-2-oxabicyclo[4.3.0]nonane-8-one-7-yl]heptanoicacid

The compounds of the present invention possess some pharmacologicalactivities such as bronchodialator.

The above described bi-cyclic compound may prepared according to thegeneral process set forth below: Preparation of Isopropyl7-[(1S,3R,6S,7R)-3-heptyl-3-hydroxy-bi-cyclo[4.3.0]nonane-8-one-7-yl)hept-5-enoateand Isopropyl 7-(1S,3R,6S,7R]-3-heptyl-3-hydroxy-bicyclo[4.3.0]nonane-8-one-7-yl]hept-5-enoate

1. Preparation of Isopropyl(Z)-7-[1R,2R,3R,5S]-2-(3,3-ethylenedioxydecyl)-5-hydroxy-3-(p-toluensulfonyl)cyclopentyl)hept-5-enoate (2)

To a mixture of pyridine (0.77 g) andisopropyl(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-(3,3-ethylenedioxydecyl)cyclopentyl]hept-5-enoate(1) (4.05 g) in dichloromethane, a solution of tosyl chloride (1.86 g)in dichloromethane was added at 0° C., and stirred for 2 days at thetemperature. During the reaction, each tosyl chloride (5.58 g) andpyridine (2.31 g) was added in three portions. After the usual work-up,the crude product was chromatographed on silica gel to give isopropyl(Z)-7-[(1R,2R,3R,5S)-2-(3,3-ethylenedioxydecyl)-5-hydroxy-3-(p-toluenesulfoxy)cyclopentyl]hept-5-enoate(2). Yield 3.45 g, 64.1%.

2. Preparation of Isopropyl(Z)-7-[(1R,2S)-2-(3,3-ethylenedioxydecyl)-5-oxocyclopent-3-enyl]hept-5-enoate(3)

Isopropyl(Z)-[1R,2R,3R,5S]-2-(3,3-ethylenedioxy-decyl)-5-hydroxy-3-(p-toluenesulfoxy)cyclopentyl]hept-5-enoate(2) (1.72 g) was oxidized in acetone at −40° C. to −20° C. with Jonesreagent for 4 hours. After the usual work-up, the crude product waspassed through silica gel pad with n-hexane/ethyl acetate (3.5/1). Theproduct was further chromatographed on silica gel (n-hexane/ethylacetate=4/1). Isopropyl(Z)-7-[(1R,2S)-2-(3,3-ethylenedioxydecyl)-5-oxo-cyclopent-3-enyl]hept-5-enoate(3) was obtained. Yield 0.81 g, 64.6%.

3. Preparation ofIsopropyl-7-[(1R,2S,3R)-2-(3,3-ethylenedioxydecyl]-3-hydroxymethyl-5-oxocyclopentyl]hept-5-enoate(4)

Isopropyl(Z)-7-[(1R,2S)-2-(3,3-ethylenedioxydecyl)-5-oxo-cyclopent-3-enyl]hept-5-enoate(3) (0.81 g) and benzophenone were dissolved in methanol. Under argonatmosphere, the solution was irradiated with 300-W high-pressure mercurylamp for 4 hours and 40 minutes. After evaporation of the solvent, thecrude product was chromatographed on silica gel (n-hexane/ethylacetate=3/2) to giveisopropyl-7-[(1R,2S,3R)-2-(3,3-ethylenedioxydecyl)-3-hydroxymethyl-5-oxocyclopentyl]hept-5-enoate(4). Yield 0.41 g, 47%.

4. Preparation ofIsopropyl-7-(1R,2S,3R)-2-(3,3-ethylenedioxydecyl)-5-oxo-3-(p-toluenesulfoxymethyl)cyclopentyl]hept-5-enoate(5)

Isopropyl-(1R,2S,3R)-2-(3,3-ethylenedioxydecyl)-3-hydroxymethyl-5-oxocyclopentyl]hept-5-enoate(4) (0.21 g) and pyridine (0.07 g) were dissolved in dichloromethane. Tothis solution, tosyl chloride (0.17 g) was added at 0° C., and themixture was stirred for 72 hours. After the usual work-up, the crudeproduct was chromatographed on silica gel to give isopropyl7-(1R,2S,3R)-2-(3,3-ethylenedioxydecyl)-5-oxo-3-(p-toluenesulfoxy)methylcyclopentyl]hept-5-enoate(5). Yield 0.25 g, 89%.

5. Preparation ofIsopropyl-7-[(1R,2R,3R)-2-(3,3-ethylenedioxydecyl)-3-iodemethyl-5-oxocyclopentylhept-5-enoate (6)

Isopropyl7-(1R,2S,3R)-2-(3,3-ethylenedioxydecyl)-5-oxo-3-(p-toluenesulfoxy)methylcyclopentyl)hept-5-enoate(5) (0.25 g) was dissolved in acetone, and sodium iodide (0.12 g) wasadded. The mixture was refluxed for 3 hours. Sodium iodide (0.097 g) wasadded to the mixture, and the mixture was refluxed for additional 80minutes. After the usual work-up, the crude product was chromatographedon silica gel (n-hexane/ethyl acetate=5/1) to give isopropyl7-(1R,2R,3R)-2-(3,3-ethylenedioxydecyl)-3-iodemethyl-5-oxocyclopentyl]hept-5-enoate(6). Yield 0.16 g, 68%.

6. Preparation of Isopropyl7-(1R,2R,3R)-3-iodemethyl-5-oxo-2-(3-oxodecyl)cyclopentyl]hept-5-enoate(7)

Isopropyl7-(1R,2R,3R)-2-(3,3-ethylenedioxydecyl)-3-iodemethyl-5-oxocyclopentyl)hept-5-enoate(6) (0.16 g) was dissolved in a mixed solvent of aceticacid/water/tetrahydrofuran (3/1/1). The mixture was stirred for 20 hoursat room temperature and for 2.5 hours at 50° C. After evaporation of thesolvent, the obtained residue was chromatographed on silica gel(n-hexane/ethyl acetate=1/1) to give isopropyl7-(1R,2R,3R)-3-iodemethyl-5-oxo-2-(3-oxodecyl)cyclopentyl]hept-5-enoate(7). Yield. 0.13 g; 86%.

7. Preparation of Isopropyl7-(1S,3S,6S,7R)-3-heptyl-3-hydroxy-bicyclo[4.3.0]nonane-8-one-7-yl]hept-5-enoate(8a) and Isopropyl7-(1S,3R,6S,7R)-3-heptyl-3-hydroxy-bicyclo[4.3.0]nonane-8-one-7-yl]hept-5-enoate(8b)

Isopropyl7-(1R,2R,3R)-3-iodemethyl-2-(3-oxodecyl)-5-oxocyclopentyl]hept-5-enoate(7) (0.0574 g) and zirconocene dichloride were dissolved intetrahydrofuran. The mixture was sonicated under argon stream to purgethe air out from the mixture. To the mixture samarium iodide intetrahydrofuran (0.1 M, 2.1 ml) was added dropwise. The mixture wasstirred for 30 minutes at room temperature, and then hydrochloric acid(0.1M, 1 mL) was added. After the usual work-up, the crude product waschromatographed on silica gel (n-hexane/ethyl acetate=5/1). Two bicyclicproducts, more polar (8a) and its epimer, less polar (8b) and startingmaterial (7) were obtained as follows:

Isopropyl 7-(1S,3S,6S,7R)-3-heptyl-3-hydroxy-bicyclo[4.3.0]nonane-8-one-7-yl]hept-5-enoate (8a) and Isopropyl7-(1S,3R,6S,7R)-3-heptyl-3-hydroxy-bicyclo[4.3.0]nonane-8-one-7-yl)hept-5-enoate(8b): Yield 8(a) 5.1 mg, Yield 8(b) 7.2 mg, Recovery of startingmaterial (7) 26.7 mg.

A theoretical synthesis for a compound represented by Formula (I) whereZ is a sulfur atom and —W₁ is an —OH group is set forth below;

A theoretical synthesis for a compound represented by Formula (I) whereZ is a sulfur atom and W₁ is a keto is set forth below:

A theoretical synthesis for a compound represented by Formula (I) whereZ is a sulfur atom, W₁ is a keto and X₁ and X₂ are fluorine atoms is setforth below:

A theoretical synthesis for a compound represented by Formula (I) whereZ is a nitrogen atom is set forth below:

Another theoretical synthesis of a compound represented by Formula (I)where Z is a nitrogen atom is set forth below:

The preparations in the present invention are not construed to belimited to them, and suitable means for protection, oxidation, reductionand the like may be employed.

The composition of the present invention comprises the above describedbi-cyclic compound and a glyceride. Examples of the glyceride used inthe present invention include a glyceride of a saturated or unsaturatedfatty acid which may have a branched chain. Preferred fatty acid is amedium chain or higher chain fatty acid having at least C6, preferablyC6-24 carbon atoms, for example caproic acid (C6), caprylic acid(C8),capric acid(C10), lauric acid(C12) and myristic acid (C14), palmiticacid(C16), palmitoleic acid(C16), stearic acid(C18), oleic acid(C18),linoleic acid(C18), linolenic acid(C18), ricinolic acid(C18) and arachicacid(C20).

In addition, 2 or more glycerides may be used as a mixture.

Examples of the mixture of glycerides are mixture of caprylic acidtriglyceride and capric acid triglyceride, vegetable oils such as castoroil, corn oil, olive oil, sesame oil, rape oil, salad oil, cottonseedoil, camellia oil, peanut oil, palm oil, sunflower oil.

The composition of the present invention may be generally prepared bydissolving or admixing the above-disclosed bi-cyclic compound in theglyceride. When it is difficult to dissolve the bi-cyclic compounddirectly in the glyceride, each of them may be dissolved in a solvent inwhich both of them are soluble respectively, and then the solutions maybe combined. In this embodiment, the solvent may be removed undervacuum.

According to the present invention, the amount of the glyceride relativeto that of the bi-cyclic compound is not limited in so far as the objectof the invention, that is, stabilization of the bi-cyclic compound isattained. Generally, 1-5,000,000 parts by weight, preferably,5-1,000,000 parts by weight, and more preferably, 10-500,000 parts byweight of the glyceride may be employed per one part by weight of thebi-cyclic compound.

The composition of the present invention may comprise the other oilsolvent. Examples of the other oil solvents may include mineral oilssuch as liquid paraffin and light liquid paraffin, tocopherol, and thelike.

The ratio of the glycerides to the other oil solvent is not limited. Theglycerides may present in an amount that improve at least the stabilityof the bi-cyclic composition of the present invention. The ratio of theglycerides in total oil solvent is at least 1 v/v %, preferably not morethan 5 v/v %.

In a preferred embodiment, the composition of the present invention issubstantially free of water. The term “substantially free of water”means that the composition does not contain water that is intentionallyadded. It is understood that many materials contain water that is takenup from the atmosphere or is present as a coordination complex in itsnormal state. Water taken up by hygroscopic materials or present as ahydrate is permissibly present in the compositions of this embodiment.According to the embodiment, any water that is present in thecomposition should not be present in amounts such that the water willhave a deleterious effect to the composition of the present invention.

The composition of the present invention may further containphysiologically acceptable additives which do not provide adverse effectto the stability of the compound of the formula (I). The additives whichmay be employed in the present invention include, but not limited to,excipients, diluents, fillers, solvents, lubricants, adjuvants, binders,disintegrants, coatings, capuslating agents, ointment bases, suppositorybase, aerozoles, emulsifiers, dispersing agents, suspensions, viscosityincreasing agents, isotonic agents, buffers, analgesic agents,preservatives, anti-oxidants, corrigents, flavors, colorants, andfunctional agents such as cyclodextrin, biologically degradablepolymers. The details of the additives may be selected from thosedescribed in any of general textbooks in the pharmaceutical field.Further, the composition of the present invention may further containanother pharmaceutically active ingredient.

The composition of the present invention may be formulated by aconventional manner. They may be in the form suitable for oraladministration, suppository, injection, or topical administration suchas eye drops or ointments. Especially, compositions suitable for oraladministration such as capsulated compositions and compositions suitablefor topical administration such as eye drops are preferable.

The present invention will be explained in more detail by means of thefollowing examples, which are illustrated by way of example only andnever intended to limit the scope of the present invention.

EXAMPLE 1

The above-described compounds 1 and 2 were dissolved in the medium chainfatty acid triglyceride (MCT)³⁾ at the amount shown in the table 1 belowrespectively. Each of the solutions was placed in a container made ofhard glass and stored at 40° C. The time-course of the content of thecompound 1 and 2 in the solutions were determined by HPLC method. Themedium chain fatty acid triglyceride used herein was a mixture ofcaprylic acid triglyceride and capric acid triglyceride (85:15). At thesame time, each of the compounds 1 and 2 was placed solely (withoutbeing dissolved in the solvent) in the container as above and stored at40° C. to provide control study.

(1) Under the absence of the solvent, the content of the compound wasdetermined as follows(HPLC method).

The stored compounds 1 and 2, and standard compounds 1 and 2 wereweighed precisely around 0.025 g each, and exactly 5 ml aliquots of aninternal standard solution were added to the respective weighedcompounds. Then the test and standard preparations were obtained byadding acetonitrile (liquid chromatograph grade) to give the precisetotal amount of 10 ml each. Each 10 μl of the test and standardpreparations was loaded on liquid chromatograph and determined thecontent of the compound by internal standard method with one pointcalibration curve.

${{content}\mspace{14mu} (\%)} = {\frac{Q_{T}}{Q_{S}} \times W_{s} \times \frac{100}{W_{T}}}$

W_(s): The amount of the compound in the standard preparation(mg)W_(T): The amount of the compound 1 or 2 in the test preparationQ_(S); Peak area ratio of the compound in the standard preparation tothe internal standard.Q_(T): Peak area ratio of the compound in the test preparation to theinternal standard.

Measurement Conditions

Detector: Ultraviolet absorption spectrophotometer (wavelength: 294 nm)Column: A stainless tube having about 5 mm of internal diameter andabout 25 cm of length, packed with 5 μm octadecylsilyl silica gel forliquid chromatographColumn temperature: Stable at around 35° C.Mobile phase: Mixed solution of acetonitrile(liquid chromatographgrade)/aqueous sodium acetate (0.01 mol/l)/glacial aceticacid(800:200:1)(2) Under the presence of the solvent, the content of the compound wasdetermined as follows (HPLC method).

Based on the value expressed in the table 1, an amount of the solutioncorresponding to 36 μg of the compound 1 or 2 was weighted precisely.Precisely 1.0 ml of an internal standard solution was added, and thenethyl acetate (liquid chromatograph grade) was added to give the totalamount of 10 ml each. Each 0.1 ml of the solution was vacuumconcentrated to dryness to give the test preparation.

Each 18 mg of the respective standard compounds was weighted preciselyand admixed with ethyl acetate (liquid chromatograph grade) to give thetotal amount of exactly 50 ml each. One (1.0) ml of the solution and10.0 ml of the internal standard solution were measured precisely andadmixed with ethyl acetate (liquid chromatograph grade) to give thetotal amount of 100 ml each. Each 0.1 ml of the solution was vacuumconcentrated to dryness to give the standard preparation.

To the test and standard preparations, 0.1 ml of fluorescent labelingreagent and 0.85 ml of fluorescent labeling catalyst were addedrespectively, and the mixture was stirred and reacted at roomtemperature more than 30 minutes. 0.05 ml aliquots of acetonitrile(liquid chromatograph grade) containing 2% acetic acid were added to thereaction mixtures respectively, stirred and then stand for more than 30minutes to provide test and standard solutions.

Each 10 μl of the test and standard solutions was loaded on liquidchromatograph and determined the content of the respective compounds byinternal standard method with one point calibration curve.

${{content}\mspace{14mu} (\%)} = {\frac{Q_{T}}{Q_{S}} \times W_{s} \times \frac{100}{18}}$

W_(S): The amount of the compound in the standard preparation(mg)Q_(S): Peak area ratio of the compound in the standard preparation tothe internal standardQ_(T): Peak area ratio of the compound in the test preparation to theinternal standard.

Measurement Condition

Detector: fluorescent spectrometer (excitation wavelength 259 nm,fluorescent wavelength 394 nm)Column: A stainless tube having about 5 mm of internal diameter andabout 25 cm of length, packed with 5 μm octadecylsilyl silica gel forliquid chromatographColumn temperature: Stable at around 35° C.Mobile phase: Mixed solution of acetonitrile(liquid chromatographgrade)/methanol (liquid chromatograph grade)/aqueous ammonium acetate(0.05 mol/l) (4:11:5)The results are shown in Table 1 below.

TABLE 1 Time course of the contents of the compounds 1 and 2 stored at40° C. (%) compound solvent initial 6 days 7 days 14 days 28 days 38days 90 days 191 days compound 1 crystal 100 — 97.2 94.1 87.4 — — —MCT¹⁾ 100 — — 101.4 — 102.1 100.9 — compound 2 crystal 100 84.5 — 75.053.4 — — — MCT²⁾ 100 — — 99.6 98.9 — — 99.6 ¹⁾compound 1/solvent: 0.36mg/g ²⁾compound 2/solvent: 0.12 mg/g 3) mixture of caprylic acidtriglyceride and capric acid triglyceride (85:15)

From the results shown in Table 1, it was proved that the stability ofthe compounds 1 and 2 were significantly improved by admixing the samewith the glyceride according to the present invention.

EXAMPLE 2

The above-described compound 1 was dissolved in various solvents at theamount shown in the table 2 below respectively. Each of the solutionswas placed in a container made of low-density polyethylene (LDPE), hardglass or stainless steel and stored at 40° C. The content of thecompound 1 in the solutions after four weeks were determined by HPLCmethod according to the above described (2) of Example 1 except forusing composition shown in table 2 below.

The results are shown in Table 2 below.

TABLE 2 Stability of the compound 1 stored at 40° C. for 4 weeks invarious solvent % to the initial conc. of compound 1 solvent container 4weeks after 10 μg/mL MCT¹⁾ LDPE²⁾ 100.8 20 μg/mL MCT Hard glass 99.5 20μg/mL MCT Stainless steel 99.5 20 μg/mL Caster oil LDPE 102.9 20 μg/mLCorn oil LDPE 99.6 20 μg/mL Olive oil LDPE 99.0 20 μg/mL Sesame oil LDPE100.1 20 μg/mL Diluted water Hard glass 39.6 10 μg/mL Saline Hard glass18.0 ¹⁾MCT: mixture of caprylic acid triglyceride and capric acidtriglyceride (85:15) ²⁾LDPE: low-density polyethylene

From the results shown in Table 2, it was proved that the stability ofthe compound 1 were significantly improved by admixing the same with theglyceride according to the present invention.

EXAMPLE 3

The above-described compound 1 was dissolved in various ratio of MCT toMineral oil at the amount shown in the table 3 below respectively. Eachof the solutions was placed in a container made of LDPE and stored at40° C. The content of the compound in the solutions after four weekswere determined by HPLC method according to the above described (2) ofExample 1 except for using composition shown in table 3 below.

TABLE 3 Stability of the compound 1 stored at 40° C. for 4 weeks invarious ratio of MCT to Mineral oil MCT/MO¹⁾ % to the initial conc. ofcompound 1 (V/V) 4 weeks after 0.7 μg/mL  0/100 88.3 0.5 μg/mL 1/99 91.00.5 μg/mL 2/98 96.6 0.5 μg/mL 5/95 98.1 0.5 μg/mL 10/90  99.0  10 μg/mL50/50  101.9 ¹⁾MO: mineral oil

From the results shown in Table 3, it was proved that the stability ofthe compound 1 were significantly improved by admixing the same with themixture of glyceride and other oil solvent according to the presentinvention.

FORMULATION EXAMPLE 1 Capsule

Fifty (50) micrograms of compound 1 was dissolved in MCT to give totalamount of 100 mg, and filled in a capsule in the conventional way togive a capsule form.

FORMULATION EXAMPLE 2 Eye Drops

Two point five (2.5) micrograms of compound 1 was dissolved inMCT/Mineral oil (20:80) to give total volume of 5 ml. The solution wasfilled in an eye-drop container to give an eye drop composition.

1. A pharmaceutical composition for oral administration comprising: i.the following bicyclic compound,

7-[(1R,6R,7R)-3-[(3S)-1,1-difluoro-3-methylpentyl]-3-hydroxy-2-oxabicyclo[4.3.0]nonane-8-one-7-yl]heptanoicacid ii. the monocyclic tautomer of said compound, and iii. aphysiologically acceptable additive, wherein the composition is suitablefor oral administration, wherein the ratio of the bicyclic compound tothe monocyclic tautomer in the pharmaceutical composition is at least90:10, wherein the composition is substantially free of water.
 2. Thecomposition according to claim 1, wherein the ratio of bi-cycliccompound to mono-cyclic tautomer is at least about 96:4.
 3. Thecomposition according to claim 1, wherein the ratio of bi-cycliccompound to mono-cyclic tautomer is substantially 100:0.
 4. Thecomposition according to claim 1, which is formulated as a capsule. 5.The composition according to claim 1, wherein said additive is an oilsolvent other than glyceride.
 6. The composition according to claim 5,wherein said oil solvent is mineral oil.